The role of the protocadherin Mucdhi in colorectal cancer

Protocadherins are predominantly expressed in the nervous system and constitute the largest subgroup of the cadherin protein superfamily. Consistently, they have been associated with neurological disorders such as Alzheimers disease, autism or schizophrenia. However, the identification of protocadherin gene deletions or silencing of protocadherin expression by promoter hypermethylation in various types of cancer has suggested that they are also implicated in oncogenesis. We focus on functions of the protocadherin Mucdhl that displays an unusual expression pattern in the gastrointestinal system and is present on the apical surface of enterocytes. We found that Mucdhl is downregulated in primary colorectal tumors (CRCs), CRC liver metastases and various CRC cell lines. Lentiviral knock-down in Caco2 cells and subsequent transplantation experiments into immunocompromised mice suggested a tumor-suppressive function for Mucdhl. Based on these results, we generated mice with floxed Mucdhl alleles. Interestingly, neither conditional inactivation in the intestinal epithelium nor germline deletion of Mucdhl using Cre deleter mice interfered with animal growth and survival suggesting that Mucdhl is dispensable for mouse development. In this proposal, we suggest to use Mucdhl-deficient mice for investigation of Mucdhl functions in intestinal tumors.

Colorectal cancer (CRC) is the third most common cancer worldwide and patients with metastases have a 5-year survival rate below 13%. Conventional cancer therapies like chemotherapy or radiotherapy are treatment options but they have a limited efficacy and are associated with severe side effects such as colitis. Therefore, it is necessary to identify novel molecules that can be used for development of targeted cancer therapies. Our research group investigated the role of the cell surface protein MUCDHL in colorectal cancer within the framework of a FWF project. We found that MUCDHL is downregulated in human colorectal tumors and metastases. Downregulation was also observed in other human cancers of the gastrointestinal system with in silico analysis of publically available internet cancer databases. We performed xenotransplantation experiments and used chemical protocols for induction of colorectal tumors in mice with germline deletion (knock-out) of MUCDHL to unravel the function of the protein in intestinal tumorigenesis. These studies revealed that MUCDHL inhibits aggressiveness of colorectal tumors. Moreover, tumors and the normal mucosa of MUCDHL knock-out mice contained significantly more epithelial cells with a secretory function. This phenotype is typical for blunted Notch signaling. Indeed, mechanistic studies demonstrated that MUCDHL activates Notch signaling in colorectal tumors and the normal gut epithelium. Since Notch is not only implicated in tumorigenesis but also in mucosal regeneration, our data demonstrate that MUCDHL represents a target for colorectal cancer therapy as well as a protective molecule during colitis that is caused by conventional cancer therapies.